IndraLab

Statements


VCP activates ATXN3. 18 / 19
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"Here, we sought to investigate whether VCP and p97 or hHR23A, both of which are involved in protein degradation pathways, also enhanced ataxin-3 activity through direct interactions."

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"Nevertheless, we sought to investigate whether VCP and p97 similarly stimulated the protease activity of expanded ataxin-3."

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"In that case, VCP appeared to increase the toxicity of the SCA3 protein by enhancing its aggregation in various fly tissues (Johnson et al., 2021; Ristic et al., 2018)."

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"The same study also showed that recombinant VCP stimulates fibrillogenesis and aggregation of recombinant, pathogenic ataxin-3 in a dose dependent manner in reconstituted systems, but only up to a point; molar excess VCP suppresses ataxin-3 fibrillogenesis."

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"VCP stimulation of ataxin-3 activity might compensate the lack of substrate and the slight inhibitory effect of hHR23A, originating similar total amounts of reaction products."

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"In conclusion, we observe decreased toxicity from ataxin-3 when VCP is knocked down in fly eyes, indicating that VCP enhances ataxin-3 aggregation and toxicity."

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"This result validates the direct VCP stimulation of wild-type ataxin-3."

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"Valosin Containing Protein (VCP and p97) Is an Activator of Wild-Type Ataxin-3."

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"Binding to VCP increases ataxin-3 deubiquitylase activity resulting in Beclin1 stabilization (Figure 2B)."

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"Importantly, VCP could induce autophagy by facilitating the de-ubiquitinase activity of ataxin-3 towards Beclin-1 or regulating the assembly and activity of the Beclin-1-containing phosphatidylinositol-3-kinase (PI3K) complex [27]."

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"However, inactivation of p97 by chemical inhibition or siRNA‐mediated ATX3 depletion again strongly induced RNF8 accumulation at the sites of IR or two‐photon micro‐irradiation DNA lesions in fixed or living cells, respectively (Fig EV2K and L)."

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"VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex."

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"We previously reported that VCP, a homo-hexameric protein, enhances pathogenic ataxin-3 aggregation and exacerbates its toxicity."

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"VCP and p97 enhances wild-type ataxin-3 activity in vitro."

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"As shown in XREF_FIG, no reaction products were detected, demonstrating that VCP and p97 enhances ataxin-3 enzymatic activity rather than act directly on ubiquitin chains."

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"Through this interaction, VCP modulates the fibrillogenesis of pathogenic forms of Atx-3 in a concentration dependent manner, with low concentrations of VCP stimulating fibrillogenesis and excess concentrations suppressing it."

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"VCP and p97 does not enhance ubiquitin hydrolase activity of expanded ataxin-3."

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"VCP also stabilized Beclin 1 and promoted autophagy in bladder cancer cells by downregulating ataxin-3."